Patent EA-002828-B1 (EA)
Title: 2,4,4-trisubstituted -1,3-dioxolane antifungals
Inventor: MEERPOEL LIEVEN
IPC: A61K31/44
Filed: 1998-07-07
Abstract: 1. A compound having the formula   a N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein n is zero, 1, 2 or 3; X is N or CH; each R<1> independently is halo, nitro, cyano, amino, hydroxy, C1-4alkyl, C1-4alkyloxy or trifluoromethyl; R<2> is hydrogen; C3-7alkenyl; C3-7alkynyl, aryl; C3-7cycloalkyl; C1-6alkyl or C1-6alkyl substituted with hydroxy, C1-4alkyloxy, C3-7cycloalkyl or aryl; R<3> and R<4> each independently are hydrogen, C1-6alkyl, C3-7cycloalkyl or aryl; or R<3> and R<4> taken together form a bivalent radical -R<3>-R<4>- of formula:   wherein R<5a>, R<5b>, R<5c>, R<5d> each independently are hydrogen, C1-6alkyl or aryl; and aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, nitro, cyano, amino, hydroxy, C1-4alkyl, C1-4 alkyloxy or trifluoromethyl. 2. A compound as claimed in Claim 1 wherein n is 1 or 2 and each R<1> independently is halo. 3. A compound as claimed in Claims 1 or 2 wherein R<3> and R<4> are independently hydrogen or C1-6alkyl, or R<3> and R<4> form a bivalent radical -R<3>-R<4>- of formula (a), (b), (c), (d) or (e). 4. A compound as claimed in any one of Claims 1 to 3 wherein R<2> is C3-7cycloalkyl or C1-6alkyl. 5. A compound as claimed in any one of Claims 1 to 4 wherein the substituents on the 1,3-dioxolane ring have a cis-configuration. 6. A compound as claimed in any one of Claims 1 to 5 wherein the phenyl ring attached in the 4-position of the 1,3-dioxolane ring is a 2,4-difluorophenyl ring; R<3 >and R<4> form a bivalent radical -R<3>-R<4>- of formula (c) wherein R<5a>, R<5b>, R<5c> and R<5d >are hydrogen; and R<2> is methyl, ethyl, propyl, butyl, 1-methylethyl or 1-methylpropyl. 7. A compound as claimed in any one of Claims 1 to 6 for use as a medicine. 8. Use of a compound as claimed in any one of Claims 1 to 6 in the manufacture of a medicament for treating fungal infections. 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as claimed in any one of Claims 1 to 6. 10. A process of preparing a compound as claimed in Claim 1, characterized with O-alkylating an appropriately substituted phenol of formula (III) with an alkylating reagent of formula (II)   wherein W represents an appropriate reactive leaving group, and n, X, R<1> to R<4> are as defined in Claim 1, in a suitable reaction-inert solvent in the presence of an appropriate base and optionally under an inert atmosphere; and, if desired, converting compounds of formula (I) into each other following artknown transformations; and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; and, if desired, preparing stereochemically isomeric forms or N-oxide forms thereof. 11. A process of preparing a compound as claimed in Claim 1, characterized with reacting an intermediate of formula (XVII) with an isocyanate R<2>-N=C=O in a reaction-inert solvent, thus obtaining a compound of formula (I-a);   wherein n, X, R<1> to R<3> are as defined in Claim 1; thus obtaining a compound of formula (I-a); and, if desired, converting compounds of formula (I) into each other following artknown transformations; and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; and, if desired, preparing stereochemically isomeric forms or N-oxide forms thereof. 12. A product containing a compound of formula (I) as defined in Claim 1, and another antifungal compound. 13. A combination as claimed in Claim 12 for use as a medicine. 14. The combination of (a) a compound of formula (I) as defined in Claim 1 and (b) another antifungal compound for simultaneous, separate or sequential use in antifungal treatment. 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I) as defined in Claim 1, and (b) another antifungal compound.